This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite decades of imaging research, the brain basis of major depression remains ill-defined. Limited understanding of the underlying mechanisms has resulted in a trial and error approach to treatment which can result in prolonged delays and exposure to potentially avoidable side-effects. This study proposes using a novel imaging approach, resting-state functional connectivity to 1) enhance our understanding of the brain bases of the affective and cognitive symptoms of depression and 2) develop an objective fMRI biomarker of depression that will predict response to treatment before or shortly after starting an antidepressant. Using independent component analysis of resting-state fMRI data, functional connectivity will be assessed separately in three brain networks that we have previously related to mood, anxiety, and executive function. Thirty drug-free patients with depression will be scanned at baseline, at one week, and at eight weeks after treatment with citalopram. Brain network connectivity in the baseline depressed state will be compared to network connectivity in thirty healthy controls using a two-sample t-test. Baseline network connectivity in the depressed subjects will be correlated against measures of mood, anxiety, and cognition to explore relationships between distinct networks and distinct symptoms of depression. Baseline scans of responders and non-responders will be compared using a two-sample t-test to search for patterns of brain network connectivity that can predict treatment response or failure. Finally, paired t-tests, performed separately in responders and non-responders, will compare changes in network connectivity between the baseline scan and the one-week and eight-week scans to determine if early network changes seen at one week can predict subsequent clinical outcome at eight weeks. Meeting the goals of this study will advance our understanding of the brain bases of depression and allow for concrete clinical applications of fMRI in its treatment.